1. Field of the Invention
The present invention relates generally to the fields of microbiology, immunology and virology. More particularly, it concerns live, attenuated Coronaviridae vaccines and methods for preventing or limiting Coronaviridae infections.
2. Description of Related Art
Coronaviruses have been long known to cause important diseases in a wide variety of animal species, including humans, cattle, swine, chickens, dogs, cats and mice. Coronavirus diseases in non-human species may be quite severe, and devastating in domestic livestock such as pigs, cattle and chickens. The characterized human coronaviruses—HCoV-229E and HCoV OC43—are significant causes of upper respiratory infections, responsible for 10-35% of human colds. Studies of human coronaviruses have been limited by their lack of growth in culture from primary isolates, and by the lack, until recently, of reverse genetic approaches for their study. Thus, while the human coronaviruses are arguably two of the most economically important viruses in humans, ongoing research has been pursued only by a handful of dedicated investigators.
The emergence of a new human coronavirus associated with “severe acute respiratory syndrome” (SARS) surprised many scientists and public health officials, but has highlighted characteristics of coronaviruses well known to investigators. The coronaviruses have high rates of mutagenesis and homologous RNA recombination. In fact, template switching and recombination are essential to the normal life cycle of the viruses. In addition, the species barrier for coronaviruses has been predicted to be tenuous. Studies of coronaviruses in culture have demonstrated the ability of coronaviruses to adapt for replication in cells of different species. In addition, some studies have demonstrated that the murine coronaviruses may cause disease in primates following direct inoculation into brain. Finally, coronaviruses have been proposed, based on evolutionary studies, to have acquired genes from other viruses or cells, probably by recombination events. The emergence of a new coronavirus pathogenic for humans, by either adaptation of an animal virus, or by recombination of two coronaviruses during a coinfection, is consistent with these features of coronavirus evolution, replication and maintenance in populations.
Vaccine approaches for important domestic animal coronaviruses diseases, specifically the chicken avian infectious bronchitis virus (E3V), porcine transmissible gastroenteritis virus (TGEV), canine coronavirus (CCV), bovine coronavirus (BCV) and feline infectious peritonitis virus (FIPV), have been developed or attempted over the past 20 years. The approaches to vaccine development have been based on non-targeted natural attenuation, virus expression vectors, virus inactivation, recombinant viral structural proteins, and novel approaches to deliver or adjuvant vaccines. Responses and protectivity of these vaccines have varied widely, but no vaccine has been shown to possess all of the characteristics of safety, stability and efficacy.
For FIPV, live-attenuated, inactivated, and subunit vaccines based on recombinant or purified spike protein, have not only failed to protect against FIPV disease, but have resulted in immune enhancement of infection and disease, a response disturbingly reminiscent of the result following vaccination of humans with inactivated vaccines for measles and respiratory syncytial virus. The most useful animal coronavirus vaccine has been the live-attenuated vaccine for IBV. However, efficacy is still clearly less than optimal. In addition, reversion to virulence may occur, and recombination of the vaccine strain with wild-type viruses has occurred, with disease in chickens caused by the recombinant vaccine-wild-type viruses.
For the most part, vaccines have not been pursued in the past for human coronaviruses, likely because the frequency and severity of infections could not be well defined, and the determinants for protection have not been identified. It is also known that 229E and OC43 can re-infect humans, possibly as often as every other year, suggesting that vaccine strategies may need to be targeted toward limitation of disease severity, since prevention may not be possible.
Together, the known biological properties of coronaviruses, as well as the concerns with limited protection or immune enhancement of disease by coronavirus vaccines, are compelling arguments for a new approach in the development of live, attenuated vaccines that are less subject to reversion and recombination, but possess normal pathways for infection and immune response. This need is all the more critical in light of the emerging human SARS situation.